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Characterization and gene structure of a novel retinoblastoma-protein-associated protein similar to the transcription regulator TFII-I.

ABSTRACT: Retinoblastoma protein (Rb) is an important regulator of vertebrate cell cycle and development. It functions through a direct interaction with protein factors involved in cell cycle progression and differentiation. In the present study we characterized a novel Rb-associated protein, Cream1, which bound to Rb specifically through a C-terminal region. Cream1 contained 959 amino acid residues and migrated as a protein of approx. 120 kDa on SDS/PAGE. It was a widely expressed nuclear protein with a nuclear localization signal resembling that of the large T antigen of simian virus 40. Its primary sequence was characteristic of five direct repeats that were similar to, but distinct from, those of TFII-I, a multifunctional transcription regulator. Three additional regions were also highly conserved in both proteins. Cream1 exhibited an activation activity that was attributed to its N-terminal portion when assayed in yeast. Its relationship with the muscle-enhancer-binding protein MusTRD1 further suggests a role in regulating gene expression. The structural gene, CREAM1, contained 27 exons and spanned more than 150 kb. It was located at human chromosome 7q11.23 in a region deleted for Williams' syndrome, a neurodevelopmental disease with multisystem abnormalities, implying its involvement in certain disorders. Taken together, our results suggest that Cream1 might serve as a positive transcription regulator under the control of Rb.

SUBMITTER: Yan X

PROVIDER: S-EPMC1220813 | biostudies-other | 2000 Feb

REPOSITORIES: biostudies-other

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Project description:UnlabelledModulation of host cell transcription, translation, and posttranslational modification processes is critical for the ability of many viruses to replicate efficiently within host cells. The human adenovirus (Ad) early region 4 open reading frame 3 (E4-ORF3) protein forms unique inclusions throughout the nuclei of infected cells and inhibits the antiviral Mre11-Rad50-Nbs1 DNA repair complex through relocalization. E4-ORF3 also induces SUMOylation of Mre11 and Nbs1. We recently identified additional cellular targets of E4-ORF3 and found that E4-ORF3 stimulates ubiquitin-like modification of 41 cellular proteins involved in a wide variety of processes. Among the proteins most abundantly modified in an E4-ORF3-dependent manner was the general transcription factor II-I (TFII-I). Analysis of Ad-infected cells revealed that E4-ORF3 induces TFII-I relocalization and SUMOylation early during infection. In the present study, we explored the relationship between E4-ORF3 and TFII-I. We found that Ad infection or ectopic E4-ORF3 expression leads to SUMOylation of TFII-I that precedes a rapid decline in TFII-I protein levels. We also show that E4-ORF3 is required for ubiquitination of TFII-I and subsequent proteasomal degradation. This is the first evidence that E4-ORF3 regulates ubiquitination. Interestingly, we found that E4-ORF3 modulation of TFII-I occurs in diverse cell types but only E4-ORF3 of Ad species C regulates TFII-I, providing critical insight into the mechanism by which E4-ORF3 targets TFII-I. Finally, we show that E4-ORF3 stimulates the activity of a TFII-I-repressed viral promoter during infection. Our results characterize a novel mechanism of TFII-I regulation by Ad and highlight how a viral protein can modulate a critical cellular transcription factor during infection.ImportanceAdenovirus has evolved a number of mechanisms to target host signaling pathways in order to optimize the cellular environment during infection. E4-ORF3 is a small viral protein made early during infection, and it is critical for inactivating host antiviral responses. In addition to its ability to capture and reorganize cellular proteins, E4-ORF3 also regulates posttranslational modifications of target proteins, but little is known about the functional consequences of these modifications. We recently identified TFII-I as a novel target of E4-ORF3 that is relocalized into dynamic E4-ORF3 nuclear structures and subjected to E4-ORF3-mediated SUMO modification. Here, we show that TFII-I is targeted by E4-ORF3 for ubiquitination and proteasomal degradation and that E4-ORF3 stimulates gene expression from a TFII-I-repressed viral promoter. Our findings suggest that the specific targeting of TFII-I by E4-ORF3 is a mechanism to inactivate its antiviral properties. These studies provide further insight into how E4-ORF3 functions to counteract host antiviral responses.

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Characterization and gene structure of a novel retinoblastoma-protein-associated protein similar to the transcription regulator TFII-I.

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